tbuckley/cabot-search huggingface dataset:
Tumor fraction to improve patient selection for oncology early phase clinical trials: Analysis of two precision medicine studies.
Authors: Sophie Cousin, Laila Belcaid, Kilian Trin, Arnaud Bayle, Melissa Alame, Etienne Rouleau, Isabelle Soubeyran, Ludovic Lacroix, Laura Blouin, Damien Vasseur, Simone Mathoulin-Pélissier, Carine A. Bellera, Antoine Italiano
Journal: Journal of Clinical Oncology (2023)

3005 Background: Typical entry criteria in early phase studies include expected life expectancy greater than 3 months. However, this evaluation is quite subjective and more objective and reproducible tools are needed to improve patients (pts) selection. The quantification of ctDNA shed by measuring tumor fraction (TF) has been associated with prognosis in solid tumors pts. However, prognostic implications of TF quantification have been evaluated primarily in retrospective studies and in a limited number of cancer types. We report here the first prospective evaluation of the prognostic impact of TF in 2 independent precision medicine studies enrolling pts referred to consider their eligibility to early phase trials. Methods: All consecutive adult pts with an advanced solid tumor included between December 2020 and December 2021 in 2 precision medicine studies: BIP (NCT02534649, sponsor: Institut Bergonié, Bordeaux, France) and STING (NCT04932525, sponsor: Institut Gustave Roussy, Villejuif, France). All pts underwent comprehensive genomic profiling with the 324-gene FoundationOne. TF was analyzed as a binary variable, indicating whether a specimen had TF ≥10% or TF &lt;10%. Multivariate analysis included previously validated prognostic scores: the Royal Marsden Hospital (albumin, LDH, number of metastatic sites) and the GRIm (LDH, neutrophil/lymphocyte ratio (NLR), albumin) scores as well as their individual components. Results: 1912 pts: N=965 in BIP and N=947 in STING were included. Their characteristics are described. High TF was associated with significantly worse overall survival (OS) in both BIP and STING studies. On multivariate analysis, TF was associated with worse OS (HR:2.49 [CI95%: 2.11 - 2.95, p&lt;0.001] and HR:2.52 [CI95%: 2.06 - 3.08, p&lt;0.001] in BIP and STING studies respectively) independently of the RMH and GRIM scores as well as their individual components. Conclusions: This is the first prospective analysis confirming that TF is a strong prognostic factor in pts with advanced solid tumors and represent an helpful tool in the process of patient selection for phase I trial entry. [Table: see text]
Understanding the late immune checkpoint inhibitor (ICI) symptom experience using an electronic patient reported outcomes (ePRO) app-based platform: The immunowave study.
Authors: Anissa Chan, Salene M.W. Jones, Emily Enright, Aleksandra Raczka, Vivian Nguyen, Shailender Bhatia, John A. Thompson, Sylvia Lee, Joshua Veatch, Scott S. Tykodi, Matt Lashey, Evan Thomas Hall
Journal: Journal of Clinical Oncology (2023)

e24067 Background: Chronic toxicities of ICI cancer therapy remain largely uncharacterized. With increasing use of ICIs in early cancer stages, the number of cancer patients exposed to ICI therapy will continue to increase. We undertook a smartphone app-based ePRO pilot study to examine symptom experience of patients with prior or ongoing (≥ 6 months) treatment with ICIs. Methods: Eligible patients had a history of advanced skin cancer or kidney cancer treated with ICI therapy (adjuvant or metastatic setting) with ongoing, clinician-assessed cancer control. Patients may have completed a course of ICI therapy or continued on therapy if ≥ 6 months had passed since initiation. We conducted a single-center, observational, prospective cohort study where participants completed weekly ePRO assessments measuring 11 PRO-CTCAE symptoms over 12 weeks. We assessed the feasibility of this app-based ePRO monitoring strategy (defined as the fraction of weekly assessments completed) and described the prevalence and severity of symptoms in this population. Results: Forty-seven patients (77% melanoma, 15% renal cell carcinoma, 8% non-melanoma skin cancer) consented to the study. At enrollment, 70% were on active therapy while 30% had completed therapy. 38% received adjuvant therapy and 62% were treated in a metastatic setting. The majority (N = 43, 91%) completed ≥ 1 weekly ePRO assessment (median 8, IQR 5.5-10). These 43 patients were included in the analysis. 61% (317/516) of the scheduled ePRO symptom assessments were completed. The prevalence, severity, and persistence of symptoms are noted in the Table. Fatigue and joint pain were most commonly reported (85% and 66% of assessments, respectively) and most commonly Grade ≥ 3 symptoms (23%, 20%). More than half of the patients reported persistent (present ≥ 50% of a patient’s assessments completed) symptoms of fatigue, joint pain, muscle pain, itchiness, rash, depression, anxiety, and numbness. Conclusions: Weekly app-based ePRO monitoring allowed for longitudinal assessment of symptoms with reasonable completion rates. Patients reported frequent, persistent, and sometimes severe symptoms, most notably fatigue, mental health symptoms, and musculoskeletal symptoms. This study suggests that patients during and after ICI therapy may experience high symptom burden, warranting further study in a larger population with longer study duration to identify candidate symptoms for interventions. [Table: see text]
Randomized phase 2 study of nab-paclitaxel and gemcitabine with or without tocilizumab as first-line treatment in patients with advanced pancreatic cancer (PACTO).
Authors: Inna Markovna Chen, Julia S. Johansen, Susann Theile, Kasper Madsen, Olav Dajani, Torben Lorentzen, Teresa Zimmers, Dorte Nielsen
Journal: Journal of Clinical Oncology (2023)

4147 Background: Pancreatic cancer (PC) presents one of the most aggressive malignancies for which currently available treatments are modestly effective. We report the findings of a randomized phase 2 trial (NCT02767557) to test the efficacy of gemcitabine/nab-paclitaxel (gem/nab) with or without tocilizumab (toc), as first-line treatment in patients with locally advanced or metastatic PC. Methods: Prior to randomization, a safety cohort of 6 participants received gem 1000 mg/m2, nab 125 mg/m2 (days 1, 8, and 15 of each 28-day cycle) and toc 8 mg/kg (day 1 of each cycle). Participants were then randomized 1:1 to receive gem/nab or gem/nab/toc. Patients had modified Glasgow Prognostic Score of 1 or 2 and were stratified by performance status (PS) and stage. The primary endpoint was the overall survival (OS) rate at 6 months (OS6). Secondary end points included median progression-free survival (PFS), median OS, overall response rate (ORR), and safety. Results: A total of 147 patients were treated; 141 were randomized to receive gem/nab/toc (n = 70), or gem/nab (n = 71). As of January 9, 2023, the median follow-up was 8.1 months (IQR 4.2–13.9). OS6 was 68.6 % (95% CI, 56.3-78.1) in gem/nab/toc group and 62.0% (95% CI, 49.6-72.1) in gem/nab group (p = 0.41). No significant differences in the median OS or PFS were observed between the gem/nab/toc group and the gem/nab group (OS, 8.4 versus 8.0 months; HR, 0.75; 95% CI, 0.54-1.05; p = 0.10), and (PFS, 5.6 versus 5.5 months; HR, 0.85; 95% CI, 0.61-1.20; p = 0.36). The 12, 18 and 24-month OS rates were 37.1% (95% CI, 26.0%-48.3%), 27.1% (17.4%-37.8%), 10% (4.4%-18.3%) for gem/nab/toc and 28.2% (18.3%-38.9%), 7.0% (2.6%-14.5%), 2.8% (0.5%-8.8%) for gem/nab, respectively. The ORR was 37.1% (95% CI, 25.9%-49.5%) in gem/nab/toc group and 35.2% (24.2%-47.5%) in gem/nab group. The incidence of grade 3 or higher treatment related adverse events was 88.2% in gem/nab/toc and 63.4% in gem/nab group (p &lt; 0.001). Of those, neutropenia (55.3% versus 16.9%), and thrombocytopenia (40.8% versus 11.3%) were most common. Two and one treatment-related deaths, respectively, in gem/nab/toc and gem/nab group, occurred during the study. Conclusions: In patients with advanced PC, the addition of tocilizumab to gem/nab did not result in improved OS rate at 6 months. Although more patients were alive at 18 months in the gem/nab/toc, long-term survival rates exceeding 24 months were not different between groups. The biomarkers for selection of patients who might benefit from gem/nab combined with tocilizumab are to be identified. Clinical trial information: NCT02767557 .
A randomized, double blinded, multicenter phase 3 study of platinum-based chemotherapy with or without QL1706 as adjuvant therapy in completely resected stage II-IIIb NSCLC.
Authors: Yuming Zhu, Tao Jiang, Lianghua Fang, Tao Zhang, Xiaoyan Kang, Caicun Zhou
Journal: Journal of Clinical Oncology (2023)

TPS8606 Background: Adjuvant atezolizumab is approved for PD-L1 positive stage II-IIIA NSCLC in USA and China. To date, there are few clinical studies on dual immune checkpoint inhibitors in adjuvant settings of NSCLC. QL1706, a MabPair product, is a novel bifunctional antibody containing a mixture of anti-PD-1 IgG4 and anti-CTLA-4 IgG1 antibodies. QL1706 monotherapy has demonstrated good safety and promising antitumor activity in advanced solid tumors in a phase Ia/Ib study with 518 patients, including 146 NSCLC patients. Meanwhile, in NSCLC patients with negative oncogene drivers, QL1706 plus 2 cycles of chemotherapy as first line treatment resulted in an ORR of 58.6% (17/29) and the mPFS was 6.97 months. Furthermore, in the EGFR mutant NSCLC patients who previously were treated with EGFR-TKI, QL1706 plus platinum-based chemotherapy and bevacizumab showed promising efficacy with an ORR of 64.5% (20/31). This study is designed to investigate the efficacy and safety of QL1706 or placebo plus platinum doublet chemotherapy as adjuvant treatment in stage II-IIIB NSCLC. Methods: In this phase Ⅲ, randomized, double-blind, placebo-controlled, multicenter study, 632 eligible pts, who is completely resected stage Ⅱ-Ⅲ B NSCLC (AJCC 8 th ) with negative EGFR, ALK etc, will be enrolled. Pts will be randomized 1:1 to receive QL1706 (5 mg/kg) or placebo plus chemotherapy, administered every 3 weeks (Q3W). The regimen of vinorelbine/paclitaxel plus cisplatin/carboplatin is chosen for squamous NSCLC, while pemetrexed/vinorelbine plus cisplatin/carboplatin for non-squamous NSCLC. Randomization will be stratified by PD-L1 TPS (ie, &lt; 1%, ≥1%), disease stage (stage II, III) and predominant tumor histology (ie, squamous vs non-squamous). The primary endpoint is disease-free survival (DFS) per investigators in PD-L1 TPS ≥1% pts and in all randomized pts, which will be tested hierarchically. An interim analysis is to occur when about 70% DFS events achieved in pts with PD-L1≥1%. Enrollment began in Nov, 2022. ClinicalTrials.gov NCT05487391. Clinical trial information: NCT05487391 .
Somatic hereditary gene panel analysis: A pilot study from Uzbekistan.
Authors: Zilola Avazovna Olimova
Journal: Journal of Clinical Oncology (2023)

e15044 Background: Molecular diagnostics is gaining importance in routine clinical practice. Availability of actionable genetic changes in hereditary panel of genes has acquired even larger interest. This study is an attempt evaluate the limited somatic genetic alterations in small population of Uzbek patients. Methods: Somatic tumor sample material was analyzed using FOUNDATIONONE R CDx (F1CDx) - the NGS based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations(indels), and copy numbers alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures. Our focus of hereditary panel included following genes-TP53, CDH1, PTEN, STK11, PALB2, CHEK2, ATM, NBN, BARD1, BRCA1 and BRCA2. Results: Out of 76 patients analyzed 50 were found have at list one abnormal gene from the above hereditary panel. TP53 was frequent pathogenic mutation in 50 of 76 patients. Commonest hereditary gene alterations were seen in ATM gene -12/50(6%). BRCA2 mutations existed in 7 of 50(3,5%), PTEN – 6/50(3%), PALB-2 – 4/50(2%), CHEK-2 – 5/50(2,5%), NBN – 5/50(2,5%), STK11 – 3/50(1,5%), CDH1 – 2/50(1%), BRCA1-2(1%), BARD1 – 1/50(0,5%). Some patients had multiple gene combinations. One of the patients had four gene abnormality-PTEN, PALB2, CHEK2, and BRCA2.Three patients have 3(1,5%) somatic hereditary mutations, 23(11,5%) patients have two abnormal hereditary genes and 38(19%) patients had changes in single gene only. Important actionable mutations (BRCA, PALB2 and CHEK2 were found in 15(11,4%) patients. Conclusions: This is the first exploratory analysis of somatic hereditary multi-gene panel. About 11% of the patients were found to have actionable gene mutations.
Sequencing bispecific antibodies and CAR T cell therapy in multiple myeloma with prior exposure to BCMA-targeted therapies.
Authors: Urvi Patel, Olalekan O. Oluwole, Adetola Kassim, Reena Jayani, Paul Belliveau, Bipin Savani, Bhagirathbhai R. Dholaria
Journal: Journal of Clinical Oncology (2023)

e20049 Background: In patients with heavily pretreated relapse and refractory multiple myeloma (MM), novel approaches such as immunotherapies and B-cell maturation antigen (BCMA) targeted therapies have been utilized to show favorable responses Despite these therapies however, patients continue to have disease progression leaving them with fewer options. A need exists to investigate the optimal sequencing strategies in the treatment approach for MM with novel bispecific antibodies (BsAbs) and CAR T cell therapy in patients previously exposed to BCMA-directed therapies. Methods: A comprehensive review of active clinical trials, published primary literature, and meeting abstracts was performed to gather efficacy endpoints and overall response rates (ORR) in patients receiving BsAbs or CAR T therapy with previous exposure to BCMA directed therapy. Results: A variety of BCMA and non-BCMA directed BsAbs along with CAR T cell therapy have been evaluated for ORR in patients who received previous BCMA-targeted therapies. Teclistamab, a BCMA BsAb induced an adequate response of 40% in patients who received previous BCMA directed antibody drug conjugate (ADC) or CAR-T- cell therapy, with a deepening of response observed in 28%. Elranatamab, an investigational BCMA-targeted BsAb demonstrated a preliminary ORR of 54% in a cohort of 13 pts. Talquetamab, a first in class GPRC5D BsAb induced an ORR of 50% in pts with previous BCMA-directed therapy as monotherapy and resulted in an ORR of 72% in combination with daratumumab. Cevostamab, an investigational FcRH5 directed BsAb demonstrated an adequate ORR of 47% in 20 pts who received previous BCMA-directed therapy. In parallel to evaluating responses for BsAbs, CAR T cell therapies including cilta-cel and ida-cel have also induced favorable and durable responses in their prior BCMA therapy exposed cohorts with an ORR of 60.0% and 74% respectively. Comparable safety profiles across both BCMA treatment exposed and BCMA treatment-naive cohorts were observed among all studies. Additional endpoints including minimal residual disease and incidence of infections are to be included in final results. Conclusions: This analysis indicates that sequencing BsAbs and CAR -T cell therapy after previous BCMA-targeted treatments offers meaningful clinical benefit with durable response rates in patients who have few other options. Longer follow up and larger studies are needed to further evaluate their enhanced benefit and generate greater insight for optimal sequencing strategies in heavily pretreated MM patients who have exhausted other options. [Table: see text]
Stopping study in chronic myeloid leukemia: Defining a new paradigm for Ontario CML1.
Authors: Siri Ravipati, Waffa Bakheet, Caroline M. Hamm
Journal: Journal of Clinical Oncology (2023)

e19069 Background: The National Comprehensive Cancer Network (NCCN) guidelines state that in order to safely stop tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) patients, we need access to reliable polymerase chain reaction (PCR) tests on a monthly basis (4 weeks). However, Ontario, Canada can only provide a 6-week turnaround reliably. Therefore, we aimed to test a new paradigm for safely stopping TKI treatment by monitoring molecular response every 6 weeks for 6 months instead of the recommended 4-week intervals. Methods: A prospective pilot cohort study was conducted to assess the outcome of cessation of TKI treatment in chronic-phase CML patients. Eligibility criteria includes obtaining MMR4 (4-log reduction) for 2 years and had to have been on TKI therapy for 5 years. Patients' PCR for BCR-ABL, a driver of CML, was tested every 6 weeks for 30 weeks to ensure ongoing major molecular response (MMR). The primary endpoint was successful maintenance of MMR3 (3-log reduction) or greater at 36 weeks. Secondary endpoints include incidence of withdrawal syndrome, psychological effects, and quality of life (QoL) as per the EORTC Global Quality of Life scoring system were assessed during each visit every 6 weeks for 30 weeks. The secondary endpoint was assessing whether MMR was regained once lost. Results: 18 consenting patients were enrolled, 2 were censored from data analysis as additional time is required to assess whether they regained deep molecular response after stopping, 1 patient was deemed too early to analyze. 12 of the 17 enrolled participants were able to successfully stop TKI therapy and remain in remission at 30 weeks, yielding a 71% success rate. 5 patients had relapsed and 3 successfully regained MR 3.0 with resumption of TKI therapy. Conclusions: The findings demonstrated in a small pilot study that testing at 6-week intervals is safe and effective. Most Ontario CML patients treated in large community centers and have not stopped TKI therapy based on the NCNN guidelines that recommend a 4-week testing turnaround. We plan to expand this study to other sites in Ontario and if successful, this new paradigm may enable more CML patients to stop TKI therapy in a safe manner leading to significant financial and clinical impact. Data will be updated at the time of the conference. By determining that Q6 weekly is a safe paradigm, there is potential for increased comfort in patients unable to maintain Q4 weekly testing for various reasons such as compliance or patients in rural settings. Clinical trial information: OCT1250 , CML1 .
Real-world outcomes of first-line maintenance with niraparib or bevacizumab in advanced ovarian cancer.
Authors: Anupama Vasudevan, Sandy English, Mike Gart, Taofikat Oladipo, John Hartman, Laura L. Iadeluca, Fred J. Kudrik
Journal: Journal of Clinical Oncology (2023)

e17598 Background: Niraparib and bevacizumab are the only FDA-approved first-line maintenance (1LM) therapies for advanced ovarian cancer (AOC) without a biomarker requirement. However, little information exists regarding the effectiveness of these treatments in the real world. Methods: We identified 89 AOC patients from the US-based deidentified Integra PrecisionQ database who received 1LM bevacizumab (n=31) or niraparib (n=58) following induction chemotherapy (CT) ± bevacizumab initiated between July 1, 2019, and March 31, 2021, and followed them until the data cut-off of March 31, 2022. Using the start of maintenance therapy as the index date, we examined patient characteristics, time to next treatment or death (TTNT; often used as a real-world proxy for progression-free survival), and overall survival (OS) for these treatment groups. Results: For patients who received 1LM bevacizumab, the median age was 69 years, 65% had Stage III cancer at index date, 84% had Eastern Cooperative Oncology Group (ECOG) performance status 0–1, and 87% received CT + bevacizumab as first-line therapy. For patients who received 1LM niraparib, the median age was 68.5 years, 66% had Stage III cancer at index date, 88% had an ECOG performance status of 0–1, and 79% received chemotherapy alone as first-line therapy. Only 1 bevacizumab (BRCAm) and 11 niraparib (4 BRCAm, 7 BRCAwt HRd) patients had known homologous recombination deficiency (HRd)-positive tumors. Patients treated with bevacizumab had a median TTNT of 4.5 months (mo) and a 12-month OS mark of 83.6%; for patients treated with niraparib, the corresponding values were 9.9 mo and 96.3%. Conclusions: Our study provides real-world outcomes data for newly diagnosed AOC patients receiving maintenance niraparib or bevacizumab following CT +/- bevacizumab. HRd testing results were only available for 19% of bevacizumab- and 40% of niraparib-treated patients, highlighting a need for greater testing in the real world. Future studies should examine which patient characteristics are associated with long-term survival for these and other treatment options to aid in the decision-making process. Funding: GSK215281. [Table: see text]
Phase II trial of BXCL701 and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (EXPEL-PANC).
Authors: Benjamin Adam Weinberg, Martin Gutierrez, Anteneh A. Tesfaye, Ming Tony Tan, Marcus Smith Noel, Aiwu Ruth He, Reetu Mukherji, John Marshall, Jennifer Gleim, Kerrie Bouker, Louis M. Weiner
Journal: Journal of Clinical Oncology (2023)

TPS4194 Background: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options and is thought to be a “cold” tumor that does not respond to immunotherapy, due to a tumor microenvironment (TME) consisting of a desmoplastic stroma and poor T cell infiltrate. BXCL701 is an oral synthetic dipeptide that competitively inhibits dipeptidyl peptidases DPP4, DPP8, DPP9 and fibroblast activation protein (FAP). BXCL701 exerts antitumor activity via inhibition of DPP8/9, which is associated with induction of proinflammatory cytokines, as well as inhibition of FAP, which disrupts tumor-stromal interactions. Preclinical xenograft models demonstrate synergy between BXCL701 and an anti-PD-1 monoclonal antibody, reducing tumor growth and promoting an increase in intratumoral CD4+ and CD8+ T cells and NK cells. The combination of BXCL701 and pembrolizumab is already being studied in a phase II trial in patients with prostate cancer (NCT03910660) and a multi-cohort basket study (NCT04171219). Methods: This is a phase II trial of BXCL701 administered at 0.2 mg PO BID days 1-7 and 0.3 mg BID days 8-14 during cycle 1 (21 days) followed by 0.3 mg BID days 1-14 every 21 days in all subsequent cycles, given with pembrolizumab 200 mg IV every 21 days (all cycles). The primary objective is to determine the 18-week progression-free survival rate (PFS18weeks) in patients with metastatic PDAC treated in the second-line setting. We estimate that historical 2 nd -line PFS18weeks is 30% or less; using a Simon’s two-stage (minimax) design, a type I error rate of 0.05 and power of 80% when the true response rate of 50%, we will need 19 patients in stage 1 and 20 in stage 2 (a total of 39). We plan to enroll 43 patients to account for a predicted 10% drop out of unevaluable patients. Eligible patients must have metastatic PDAC and disease progression or intolerance to only 1 line of therapy for metastatic disease, without exposure to prior immunotherapy. Patients must have measurable disease amenable to serial biopsies. Correlative pharmacodynamic studies include imaging mass cytometry to examine 34 markers of the PDAC TME in tissue biopsies, as well as blood-based analyses of KRAS circulating tumor DNA, circulating markers of fibrosis, and IL-6. Enrollment began in Q1 2023. Clinical trial information: NCT05558982 .